The present invention relates to sustained release formulations of lorazepam and to methods of treating patients with a once-a-day dose of lorazepam.
Lorazepam is the generic name for the active pharmaceutical ingredient ±7-chloro-5-(2-chlorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepin-2-one, which has the following structure:
Like other benzodiazepines, lorazepam has CNS activity and has proven to be a useful treatment for anxiety related disorders, such as: General Anxiety Disorder or Anxiety associated with Major Depression and others. It is almost insoluble in water. This compound was disclosed in U.S. Pat. No. 3,296,249.
Lorazepam has been sold commercially under the brand name ATIVAN® (originally by Wyeth, now by Valeant Intl) in the form of an oral immediate release tablet. The tablets contain 0.5 mg, 1 mg, or 2 mg of lorazepam and are usually administered two or three times a day (b.i.d and t.i.d, respectively) to achieve a total dose of 2 to 6 mg/day, though doses from 1 to 10 mg/day can also be used. According to the U.S. package insert material for ATIVAN®: “For anxiety, most patients require an initial dose of 2 to 3 mg/day given b.i.d. or t.i.d.” The peak plasma concentrations (Cmax) typically occur about 2 hours (Tmax) after oral administration. Lorazepam has, according to the package insert, a half-life in human plasma of about 12 hours.
While the immediate release tablets of lorazepam, with a multi-dose per day regimen, have been available for several decades, thus far no once-a-day dosage form has been commercially introduced. Such a dosage form is often desirable. Besides the benefit of convenience, a sustained release version that could provide 24 hour therapeutic effect, but with lower peak plasma concentration levels than the immediate release tablet, may reduce side effects. For this reason, Abrams et al. investigated a sustained release tablet containing 2 mg of lorazepam and compared it to a 2 mg dose of lorazepam immediate release tablets (2×1 mg tablets). S. M. L. Abrams et al., “Pharmacodynamic and Pharmacokinetic Comparison of Two Formulations of Lorazepam and Placebo,” Human Psychopharmacology, Vol. 3, 133-138 (1988). The sustained release tablet had, as expected, a longer Tmax (median 8 hours) and a lower Cmax (12 ng/ml) than the immediate release tablets (2 hours and 22 ng/ml, respectively). But the relative bioavailability was reduced in the sustained release tablet such that after 30 hours the AUC was only about 85% of the AUC achieved with the immediate release tablets. Abrams et al. also noted that “the [serum] concentrations of both formulations were similar between 10 and 30 h[ours].” Thus, despite providing some delay in the rise of lorazepam serum concentrations and a lower Cmax, the sustained release tablet apparently did not serve to extend the therapeutic duration of lorazepam beyond that achieved with immediate release tablets.
The long half-life of lorazepam in blood plasma makes it a classically disregarded candidate for the development of a once daily formulation. Also, a drug product that provides 24 hour therapy from two doses per day, as opposed to three or more doses per day, is generally considered to have achieved the majority of patient compliance benefits. If a single daily dose formulation was desired, an immediate release lorazepam tablet could be used to provide a complete daily dose because of the long half-life of lorazepam in blood plasma. But administering a complete daily dose in a single immediate release dosage form would increase the Cmaxand the peak-trough variations (concentration differences between Cmaxand Cmin) beyond those attained in conventional b.i.d. administration (i.e., twice-daily dosing), and thus would likely increase the risk of drug related adverse events, i.e., side effects. Using a sustained release formulation can reduce the rate of increase in plasma drug concentration and the value of Cmax, but runs the risk of sub-therapeutic plasma concentration levels, especially near the end of the dosing cycle, and/or lower overall drug exposure than the current b.i.d. immediate release tablet regimen.
A lorazepam formulation that provides a sustained release profile with the potential for an effective and well tolerated once daily dosing regimen would be advantageous.